Obesity, now affecting greater than 30% of the United States population, is an epidemic associated with diabetes, hypertension and heart disease for which there is currently no effective treatment. Decreased activity of the sympathetic nervous system (SNS) through impaired beta-adrenergic receptor (BAR) signaling has been shown to be associated with obesity. Investigations into how abnormal BAR signaling causes obesity has been complicated, however, by the presence of three BARs in adipose tissue that probably have redundant functions. Previous gene knockout studies have not determined whether BARs are necessary for fat cell development and function. In addition, it is not known how stimulation of BARs leads to induction of a thermogenic program in brown adipose tissue (BAT) via a molecule called PGC-1. These studies will investigate the role that beta-adrenergic receptors (BARs) play in the process of brown and white adipose tissue biology. We have created lines of mice that lack all 3 known BARs, and these offer an experimental paradigm to ask critical questions: is BAR signaling as a whole is necessary or sufficient for adipose metabolism; what alternative pathways exist for adipose function? Dr. Eric S. Bachman will perform this project under the guidance of Dr. Bradford Lowell in the Division of Endocrinology and Metabolism at Beth Israel Deaconess Medical Center. Dr. Lowell has made major contributions to the understanding of the molecular mechanisms that govern mammalian energy expenditure and fat metabolism. There are also numerous investigators in the division and within the Harvard Medical School community with interests in obesity, regulation of brown fat biology and signal transduction. This will provide an excellent environment for the completion of this project, and will provide a basis for Dr. Bachman's transition to an independent investigator.